The main objective of the proposed study is to investigate the role of the transcription factor, cyclic AMP response element binding protein (CREB) and a major downstream target, BDNF, in cocaine related addiction behaviors. Previous findings as well as preliminary data implicate CREB in modulating the rewarding properties of cocaine. In addition, BDNF is also implicated in facilitating sensitization and conditioned reward. Using the cocaine self-administration model in rodents, the proposed study plans to 1) investigate the 1) functional role of CREB and BDNF in the nucleus accumbens (NAc) core and shell regions in addiction-related changes in cocaine self-administration and the propensity for relapse in withdrawal, and 2) neuroadaptations in BDNF and pre- and post-synaptic markers of synaptic plasticity. Studies will test the direct effects of CREB and BDNF on cocaine self-administration on both fixed and progressive ratio schedules of reinforcement, and the possible long-term consequences on the reinstatement of cocaine seeking in withdrawal. Experiments will utilize, HSV-mediated overexpression in rats, and site-specific knockout of target genes in mice. These studies will determine the effects of up- or down regulating CREB and BDNF activity in NAc subregions on addictive behavior.